managing the menopause afterwhi 2008the women’s health initiative (whi) 1 study women who took...
TRANSCRIPT
Disclosures Consultant (Fees to UVA)
Pfizer DepoMed Noven Shionogi NovoNordiskTherapeuticsMD
Multicenter Research (Fees to UVA) DepoMed Endoceutics BionovaTherapeuticsMD
Travel fees Pfizer DepoMedNoven Shionogi NovoNordiskTherapeuticsMD
1
JoAnn V Pinkerton MD NCMP
Professor of Obstetrics and Gynecology Director Midlife Health Center
University of Virginia NAMS Past President
Individualized Treatment Options Availablemdash Appropriate Candidates Clinical Pearls Marriott Gaylord National HotelmdashWashington DC ThursmdashOctober 16 2014
Hormone Therapy Conventional and Novel
At the conclusion of this presentation participants should be able to
Understand new option compared to traditional HT Tissue Selective Estrogen Compound (TSEC)
Conjugated EstrogensBazedoxefine
Compare traditional and novel hormone therapy Choose the best therapy for the individual
symptomatic menopausal woman Differentiate on basis of bleeding and breast tenderness
between CEBZA (TSEC) and CEMPA (EPT)
The Womenrsquos Health Initiative (WHI)1 study
Women who took estrogen plus a progestin (CEEMPA EPT) for more than 5 years were at increased risk for coronary heart disease stroke venous thromboembolism and breast cancer Estrogen alone for women without a uterus did not increase the risk of coronary heart disease or breast cancer
WHI Re-analysis Effect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
50-59 Years 70-79 Years
Acute MI -12 +16 Death -13 +19 Adverse events (Global index of chronic diseases)
-18 +48
Expressed as absolute rates per 10000 women annualized over the average follow-up period of 107 years
Differences in Outcomes in Women Who Received CEE
LaCroix AZ et al JAMA2011305(13)1305-14
Reanalysis in 20072 found less risk for women under 60 and higher risks for women 70 and over
Slide Robert Reid
NAMS and IMS Guidelines ldquoNew data and re-analyses of older studies by womenrsquos age show that for most women the potential benefits of HT given for a clear indication are many and the risks are few when initiated within a few years of menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree Menopause Stuenkel Cynthia A Gass Margery LS Manson JoAnn E More Menopause 19(8)846-847 August 2012 RD Langer JA Manson MA Allison WHI Investigators Climacteric June 2012 De Villiers TJ Climacteric 201316203-204
ldquoBenefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
For younger women HT is an acceptable option for treating
moderate to severe menopausal symptoms in relatively young (up to age 59 or within 10 years of menopause) and healthy women
Individualization is key in the decision to use HT
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
JoAnn V Pinkerton MD NCMP
Professor of Obstetrics and Gynecology Director Midlife Health Center
University of Virginia NAMS Past President
Individualized Treatment Options Availablemdash Appropriate Candidates Clinical Pearls Marriott Gaylord National HotelmdashWashington DC ThursmdashOctober 16 2014
Hormone Therapy Conventional and Novel
At the conclusion of this presentation participants should be able to
Understand new option compared to traditional HT Tissue Selective Estrogen Compound (TSEC)
Conjugated EstrogensBazedoxefine
Compare traditional and novel hormone therapy Choose the best therapy for the individual
symptomatic menopausal woman Differentiate on basis of bleeding and breast tenderness
between CEBZA (TSEC) and CEMPA (EPT)
The Womenrsquos Health Initiative (WHI)1 study
Women who took estrogen plus a progestin (CEEMPA EPT) for more than 5 years were at increased risk for coronary heart disease stroke venous thromboembolism and breast cancer Estrogen alone for women without a uterus did not increase the risk of coronary heart disease or breast cancer
WHI Re-analysis Effect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
50-59 Years 70-79 Years
Acute MI -12 +16 Death -13 +19 Adverse events (Global index of chronic diseases)
-18 +48
Expressed as absolute rates per 10000 women annualized over the average follow-up period of 107 years
Differences in Outcomes in Women Who Received CEE
LaCroix AZ et al JAMA2011305(13)1305-14
Reanalysis in 20072 found less risk for women under 60 and higher risks for women 70 and over
Slide Robert Reid
NAMS and IMS Guidelines ldquoNew data and re-analyses of older studies by womenrsquos age show that for most women the potential benefits of HT given for a clear indication are many and the risks are few when initiated within a few years of menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree Menopause Stuenkel Cynthia A Gass Margery LS Manson JoAnn E More Menopause 19(8)846-847 August 2012 RD Langer JA Manson MA Allison WHI Investigators Climacteric June 2012 De Villiers TJ Climacteric 201316203-204
ldquoBenefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
For younger women HT is an acceptable option for treating
moderate to severe menopausal symptoms in relatively young (up to age 59 or within 10 years of menopause) and healthy women
Individualization is key in the decision to use HT
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
At the conclusion of this presentation participants should be able to
Understand new option compared to traditional HT Tissue Selective Estrogen Compound (TSEC)
Conjugated EstrogensBazedoxefine
Compare traditional and novel hormone therapy Choose the best therapy for the individual
symptomatic menopausal woman Differentiate on basis of bleeding and breast tenderness
between CEBZA (TSEC) and CEMPA (EPT)
The Womenrsquos Health Initiative (WHI)1 study
Women who took estrogen plus a progestin (CEEMPA EPT) for more than 5 years were at increased risk for coronary heart disease stroke venous thromboembolism and breast cancer Estrogen alone for women without a uterus did not increase the risk of coronary heart disease or breast cancer
WHI Re-analysis Effect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
50-59 Years 70-79 Years
Acute MI -12 +16 Death -13 +19 Adverse events (Global index of chronic diseases)
-18 +48
Expressed as absolute rates per 10000 women annualized over the average follow-up period of 107 years
Differences in Outcomes in Women Who Received CEE
LaCroix AZ et al JAMA2011305(13)1305-14
Reanalysis in 20072 found less risk for women under 60 and higher risks for women 70 and over
Slide Robert Reid
NAMS and IMS Guidelines ldquoNew data and re-analyses of older studies by womenrsquos age show that for most women the potential benefits of HT given for a clear indication are many and the risks are few when initiated within a few years of menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree Menopause Stuenkel Cynthia A Gass Margery LS Manson JoAnn E More Menopause 19(8)846-847 August 2012 RD Langer JA Manson MA Allison WHI Investigators Climacteric June 2012 De Villiers TJ Climacteric 201316203-204
ldquoBenefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
For younger women HT is an acceptable option for treating
moderate to severe menopausal symptoms in relatively young (up to age 59 or within 10 years of menopause) and healthy women
Individualization is key in the decision to use HT
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
The Womenrsquos Health Initiative (WHI)1 study
Women who took estrogen plus a progestin (CEEMPA EPT) for more than 5 years were at increased risk for coronary heart disease stroke venous thromboembolism and breast cancer Estrogen alone for women without a uterus did not increase the risk of coronary heart disease or breast cancer
WHI Re-analysis Effect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
50-59 Years 70-79 Years
Acute MI -12 +16 Death -13 +19 Adverse events (Global index of chronic diseases)
-18 +48
Expressed as absolute rates per 10000 women annualized over the average follow-up period of 107 years
Differences in Outcomes in Women Who Received CEE
LaCroix AZ et al JAMA2011305(13)1305-14
Reanalysis in 20072 found less risk for women under 60 and higher risks for women 70 and over
Slide Robert Reid
NAMS and IMS Guidelines ldquoNew data and re-analyses of older studies by womenrsquos age show that for most women the potential benefits of HT given for a clear indication are many and the risks are few when initiated within a few years of menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree Menopause Stuenkel Cynthia A Gass Margery LS Manson JoAnn E More Menopause 19(8)846-847 August 2012 RD Langer JA Manson MA Allison WHI Investigators Climacteric June 2012 De Villiers TJ Climacteric 201316203-204
ldquoBenefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
For younger women HT is an acceptable option for treating
moderate to severe menopausal symptoms in relatively young (up to age 59 or within 10 years of menopause) and healthy women
Individualization is key in the decision to use HT
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
WHI Re-analysis Effect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
50-59 Years 70-79 Years
Acute MI -12 +16 Death -13 +19 Adverse events (Global index of chronic diseases)
-18 +48
Expressed as absolute rates per 10000 women annualized over the average follow-up period of 107 years
Differences in Outcomes in Women Who Received CEE
LaCroix AZ et al JAMA2011305(13)1305-14
Reanalysis in 20072 found less risk for women under 60 and higher risks for women 70 and over
Slide Robert Reid
NAMS and IMS Guidelines ldquoNew data and re-analyses of older studies by womenrsquos age show that for most women the potential benefits of HT given for a clear indication are many and the risks are few when initiated within a few years of menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree Menopause Stuenkel Cynthia A Gass Margery LS Manson JoAnn E More Menopause 19(8)846-847 August 2012 RD Langer JA Manson MA Allison WHI Investigators Climacteric June 2012 De Villiers TJ Climacteric 201316203-204
ldquoBenefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
For younger women HT is an acceptable option for treating
moderate to severe menopausal symptoms in relatively young (up to age 59 or within 10 years of menopause) and healthy women
Individualization is key in the decision to use HT
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
NAMS and IMS Guidelines ldquoNew data and re-analyses of older studies by womenrsquos age show that for most women the potential benefits of HT given for a clear indication are many and the risks are few when initiated within a few years of menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree Menopause Stuenkel Cynthia A Gass Margery LS Manson JoAnn E More Menopause 19(8)846-847 August 2012 RD Langer JA Manson MA Allison WHI Investigators Climacteric June 2012 De Villiers TJ Climacteric 201316203-204
ldquoBenefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopauserdquo
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
For younger women HT is an acceptable option for treating
moderate to severe menopausal symptoms in relatively young (up to age 59 or within 10 years of menopause) and healthy women
Individualization is key in the decision to use HT
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
For younger women HT is an acceptable option for treating
moderate to severe menopausal symptoms in relatively young (up to age 59 or within 10 years of menopause) and healthy women
Individualization is key in the decision to use HT
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Women taking menopausal estrogen Women with a uterus need
endometrial protection Either combined with a progestogen TSEC- combined with SERM
Women without a uterus can take estrogen alone
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Window of Opportunity for Cardio-Protection
Tom Clarkson monkey model first
suggested timing hypothesis
Limited RCT data support
cardioprotective effect and the
timing hypothesis
Danish Osteoporosis
Prevention Study (DOPS)
Similar cardio-protective effect as HT meta-analysis
Early versus Late Intervention
Trial with Estradiol (ELITE)
Cnfirmed the laquo Timing
hypothesis raquo
Concordance with observational
studies Young
postmenopausal women who use
HRT for long periods of time
have lower rates of CHD and mortality
than comparable postmenopausal
women who do not use HRT
Hodis HN et al Climacteric 201215217-28 Adapted Robert Reid
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Risk of blood clotsstroke Both estrogen therapy and estrogen
with progestogen therapy increase the risk of VTE and PE
Although the risks of VTE and strokes increase with HT the risk is rare in the 50-59-year-old age group
In 50-59 yr olds in WHI the attributable risks were Combined MHT - 12000 WY Estrogen alone ndash no increase
Is route or dosage more important Less risk with low dose transdermal in observational studies
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Risk of breast cancer An increased risk in breast cancer
is seen in 3-5 years of continuous estrogenprogestogen therapy
The risk decreases after HT is stopped
A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Safe to use EPT or ET long term The WHI did not address
the long term effects of EPT or ET when started in newly
menopausal women
12
See Dr Kaunitzrsquos talk Thursday Plenary 4
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Women with vaginal symptoms only
The preferred treatments are low doses of vaginal estrogen
Another option is new SERM ospemifene which improved dyspareunia
Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
HT is an FDA-approved option for relief of menopausal symptoms and VVA and prevention of osteoporosis
Many FDA approved HT options including bioidentical oral and transdermal Compounded HT is not FDA
approved Adapted Pinkerton A Decade After The Womenrsquos Health InitiativemdashThe Experts Do Agree
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
NAMS Menopause 201219257-271 NAMS Website ACOG Website wwwacogorgCommittee_on_Gynecologic_PracticeCompounded_Bioidentical_Hormones
Concerns about Custom Compounded Bioidentical Hormone Therapy Not FDA APPROVED regulated or monitored
Manufacturing not overseen by FDA What exactly is in it Quality purity 70-200 estradiol 70 progesterone
No large clinical trials to test safety and effectiveness
Meningitis and deaths from compounded non sterile steroid injections
Myths abound that it is safer or prevents breast cancer Potential medicolegal risks for provider
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
HT tolerability issues HT associated with poor compliance due
to tolerability of progestogen Irregular bleeding
May increase unnecessary interventionsanxiety
Breast paintenderness May cause anxiety
Increase on breast density May reduce sensitivity of screening mammograms Independent risk factor for breast cancer
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
New hormonal option- CEEBZA (TSEC) CEEBZA is a tissue-selective estrogen complex (TSEC) pairing CE with the selective estrogen receptor modulator (SERM) BZA Unlike other SERMs BZA possesses sufficient antagonist effect on uterine tissue to be paired with an estrogen CEEBZA Endometrial protection Neutral breast Prevents hot flushes Prevents bone loss Preserves vaginal health Favorable lipid profile
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
FDA approved novel hormone therapy
In October 2013 the FDA approved a novel hormone therapy conjugated estrogens paired with the SERM bazedoxefine (CEBZA) for symptomatic postmenopausal women with a uterus to relieve hot flashes and prevent osteoporosis without the need for a progestogen Incidence of endometrial hyperplasia at year one was low lt1 and similar to placebo with rates comparable to placebo for cardiovascular and cerebrovascvular events and cancer VTE rates were low
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
CE 045BZA20 Statistically different from placebo from week 3 onward CE 0625BZA20 Statistically different from placebo from week 2 onward
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Mea
n D
aily
Num
ber
of H
ot F
lush
es
Weeks
Placebo (n=63)CE 045BZA 20 (n=123)CE 0625BZA 20 (n=122)
51
74 80
Pinkerton et al Menopause 2009161116-1124
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
SMART 2 Hot Flush Daily Severity Score Reduction in HF severity up to 54
CE 045BZA 20 and CE 0625BZA 20 Statistically different from placebo from week 3 onward
0
05
1
15
2
25
0 1 2 3 4 5 6 7 8 9 10 11 12
Da
ily
Se
veri
ty S
co
re
Weeks of Therapy
Placebo (n=63)CE 045BZA 20 (n=122)CE 0625BZA 20 (n=125)
17
37
52
Pinkerton et al Menopause 2009161116-1124
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
SMART 3 Vaginal Maturation Index
0
1
2
3
4
5
6
7
8
9
10
Screening Week 4 Week 12
S
uper
ficia
l C
ells
PlaceboCE 045BZA 20CE 0625BZA 20BZA 20
dagger
dagger
dagger
dagger SMART 3
Superficial cells
dagger dagger dagger dagger
Plt005 vs placebo daggerPlt005 vs BZA alone Plt005 vs placebo daggerPlt005 vs BZA alone Kagan et al Menopause 201017281-289
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
-1
-08
-06
-04
-02
0
02Week 4 Week 12
Vagi
nal p
H
Placebo CE 045BZA 20CE 0625BZA 20 BZA 20
Both CEBZA groups statistically different from BZA 20 at both time points
lt0001
0116 0101
lt0001
Data on file Pfizer Inc Kagan et al Menopause 201017281-289
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Lumbar Spine BMD Adjusted Mean Change
-2
-1
0
1
2
6 12
Months of Therapy
Adj
uste
d M
ean
C
hang
e
CE 0625BZA 20 (n=139) CE 045BZA 20 (n=119) BZA 20 (n=56)
Placebo (n=139) CE 045MPA 15 (n=59)
BMD change relative to PBO CE 0625BZA 20 uarr 187 at 1y CE 045BZA 20 uarr 151 at 1y BZA 20 uarr 134 at 1y CE 045MPA 15 uarr 257 at 1y
P-value vs Placebo le 0001 (both CEBZA groups BZA and CEMPA) Data on file Pfizer Inc
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Prevention Osteoporosis Summary Increase from baseline in LS and total hip BMD at year 1
and 2 Significantly higher than placebo Comparable or superior to raloxifene Comparable to BZA Comparable or inferior to CEMPA Persistence of effect up to 2 years Effective regardless of the sub-population evaluated
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Endometrial Safety Incidence of endometrial hyperplasia lt 1 as
required by regulatory agencies Low incidence of endometrial proliferation Low incidence of asymptomatic endometrial polyps Asymptomatic increase in endometrial thickness (lt
1mm) Amenorrhea similar to placebo and consistently lower
than CEMPA
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Breast Tenderness and Density Breast density -independent risk factor for breast
cancer2
EPT associated with increased breast density 1 New onset of tenderness with EPT linked to increase
in mammagraphic density 3-5
CEE-alone no increased breast tenderness or mammographic density 5-6
1 Greendale et al J Natl Cancer Inst 200395(1)30-37
2 Boyd et al J Natl Cancer Inst 199587(9)670-675
3 Bulbul et al Arch Gynecol Obstet 2003268(1)5-8
4 McNicholas et al AJR Am J Roentgenol 1994163(2)311-315
5 Crandall et al Breast Cancer Res Treat 2012131(3)969-979
6 Crandall et al Breast Cancer Res Treat 2012132(1)275-285
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
BZA bazedoxifene CE conjugated estrogens MPA medroxyprogesterone acetate aP lt0001 vs placebo bP lt001 vs BZA 20 mgCE 045 and 0625 mg and BZA 20 mg
CE 045 mgBZA 20 mg
CE 0625 mgBZA 20 mg CE 045 mgMPA 15 mg
BZA 20 mg Placebo
Data on file Pfizer Inc
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
SMART 5 Adjusted Change From Baseline in Breast Density (PP)
daggerIncludes all women enrolled in the breast density substudy who took at least 1 dose of study drug had a baseline breast density evaluation and had at least 1 post-baseline evaluation P lt0001 vs placebo
Adjusted Change From Baseline in Percent Breast Density at Year 1dagger
ndash038 (022) ndash044 (022)
ndash024 (030)
160 (035)
ndash032 (023)
CE 045 mgBZA 20 mg (n = 186) CE 0625 mgBZA 20 mg (n=191) BZA 20 mg (n=98) CE 045 mgMPA 15 mg (n=68) Placebo (n=182)
Pinkerton et al Obstet Gynecol 2013 121959-68
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Cumulative Incidence of Breast Cancer
BZA 20 mg CE 045 mg (n = 1585)
BZA 20 mg CE 0625 mg (n = 1583)
Placebo (n = 1241)
Events
4 0 2
Incidence rate per 1000 women-years (95 CI)
10 (00 32) 00 (00 15) 14 (00 42)
Relative risk (95 CI)
11 (03 38) 04 (01 20)
BZA bazedoxifene CE conjugated estrogens CI confidence interval Includes cumulative data (up to 2 years) from SMART-1 SMART-2 SMART-3 SMART-4 and SMART-5
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
SUMMARYCEE 045 and 0625 mg BZA 20 Significant reduction in menopausal symptoms Improvements in VMS156 Improvement in measures of VVA178
Significant increases in BMD and decreased bone turnover2
Low incidences of breast paintenderness1 High rates of amenorrhea similar to placebo4
Low incidences of endometrial hyperplasia3 No changes in mammographic breast density9
1Lobo RA et al Fertil Steril 200992(3)1025-1035 2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 5Pinkerton JV et al Menopause 200916(6)1116-1124
6Utian W et al Maturitas 200963(4)329-335 7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140 9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Maximize Benefits and Minimize Risks of HT
Lowest risk if begun win 1st 10 yrs of menopause or lt age 60 Primary indication is bothersome hot flashes and night sweats
Other indications include high risk osteoporosis depression not responding to antidepressants sleep disruption due to VMS Somatic pains migraines worsening with lowered estrogen
Benefit for CVD protection intriguing- Not contraindicated for symptomatic women gt60
If evaluate risk factors for CAD treat medical issues If continuing hormone therapy for women who began in their 50rsquos
Consider low dose transdermal- lower VTE and stroke risk Reassess regularly For many treatment can be tapered down or
stopped after a few years of use
Adapted Robert Reid SOCG 38
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Clinical Pearls- Traditional or TSEC Individualizing Therapy
No uterus- Estrogen alone No data indication for TSEC if hysterectomized Uterus intact- need endometrial protection Requires progestogen or TSEC Consider TSEC over conventional EPT Breast tenderness Increased breast density Concerned about breast cancer risk Bleeding Possibly after 3-5 years of EPT- no data on switching
from EPT to TSEC
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Suggested References 1Lobo RA et al Fertil Steril 200992(3)1025-1035
2Lindsay R et al Fertil Steril 200992(3)1045-1052 3Pickar JH et al Fertil Steril 200992(3)1018-1024 4Archer DF et al Fertil Steril 200992(3)1039-1044 6Utian W et al Maturitas 200963(4)329-335
7Kagan R et al Menopause 201017(2)281-289 8Bachmann G et al Climacteric 201013(2)132-140
9Harvey JA et al Endocr Rev 201132(3) Abstract P1-79 Pinkerton JV Harvey JA Lindsay R Pan K Chines AA Mirkin S Archer DF SMART-5
Investigators Effects of bazedoxifeneconjugated estrogens on the endometrium and bone a randomized trialJ Clin Endocrinol Metab 2014 Feb99(2)E189-98
Pinkerton JV Harvey JA Pan K Thompson JR Ryan KA Chines AA Mirkin S Breast effects of bazedoxifene-conjugated estrogens a randomized controlled trial Obstet Gynecol 2013 May121(5)959-68
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Stuenkel C A et al A decade after the Womens Health Initiativemdashthe experts do agree J Clin Endocrinol Metab 97 2617ndash2618 (2012)
Manson JECurrent recommendations what is the clinician to do Fertil Steril 2014 Apr101(4)916-21 doi 101016jfertnstert201402043
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Table 1 Major indications and contraindications for PMHT
Rozenberg S et al (2013) Postmenopausal hormone therapy risks and benefits Nat Rev Endocrinol doi101038nrendo201317
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-
Demographics amp Baseline Characteristics Pooled demographics for all 4 trials generally balanced
across treatment groups SMART-1
(PM) SMART-2
(VMS) SMART-3
(VVA) SMART-5
(VMS)
Age Mean (SD) 5633 (594) 5339 (476) 5633 (447) 5353 (372)
Race () White Black Hispanic Asian Other
812 136 38 08 07
814 107 38 09 31
884 35 35 15 31
841 107 38 09 06
BMI Mean (SD) 2593 (351) 2620 (400) 2539 (384) 2608 (383)
Yrs Since LMP Mean (SD)
820 (573) 454 (409) 744 (484) 359 (309)
BMI ndash Body Mass Index LMP ndash Last Menstrual Period
- Disclosures
- At the conclusion of this presentation participants should be able to
- The Womenrsquos Health Initiative (WHI)1 study
- WHI Re-analysisEffect of Estrogen Alone on Major Outcomes for Women lt60 Years vs 70-79 Years
- NAMS and IMS Guidelines
- For younger women
- Women taking menopausal estrogen
- Window of Opportunity for Cardio-Protection
- Risk of blood clotsstroke
- Risk of breast cancer
- Safe to use EPT or ET long term
- Women with vaginal symptoms only
- HT is an FDA-approved optionfor relief of menopausal symptoms and VVA and prevention of osteoporosis
- Slide Number 15
- HT tolerability issues
- New hormonal option- CEEBZA (TSEC)
- FDA approved novel hormone therapy
- SMART 2Daily Mod-Severe Hot Flushes (LOCF)-Reduction in HF number up 80
- SMART 2 Hot Flush Daily Severity ScoreReduction in HF severity up to 54
- SMART 3 Vaginal Maturation Index
- SMART 3 Adjusted Mean Change From Baseline in Vaginal pH
- Lumbar Spine BMD Adjusted Mean Change
- Prevention Osteoporosis Summary
- Endometrial Safety
- Breast Tenderness and Density
- Percentage of subjects ge1 day of breast tenderness during 4-week cycles over Year 1
- SMART 5 Adjusted Change From Baseline in Breast Density (PP)
- Cumulative Incidence of Breast Cancer
- SUMMARYCEE 045 and 0625 mg BZA 20
- Maximize Benefits and Minimize Risks of HT
- Clinical Pearls- Traditional or TSEC Individualizing Therapy
- Suggested References
- Slide Number 41
- Demographics amp Baseline Characteristics
-